Tau Secretion: Good and Bad for Neurons

Abstract

In Alzheimer's disease (AD), neurofibrillary tangles (NFTs), lesions composed of hyperphosphorylated and aggregated tau, spread from the transentorhinal cortex to the hippocampal formation and neocortex. Growing evidence indicates that tau pathology propagates trans-synaptically, implying that pathological tau released by pre-synaptic neurons is taken up by post-synaptic neurons where it accumulates and aggregates. Observations such as the presence of tau in the cerebrospinal fluid (CSF) from control individuals and in the CSF of transgenic mice overexpressing human tau before the detection of neuronal death indicate that tau can be secreted by neurons. The increase of tau in the CSF in pathological conditions such as AD suggests that tau secretion is enhanced and/or other secretory pathways take place when neuronal function is compromised. In physiological conditions, extracellular tau could exert beneficial effects as observed for other cytosolic proteins also released in the extracellular space. In such a case, blocking tau secretion could have negative effects on neurons unless the mechanism of tau secretion are different in physiological and pathological conditions allowing the prevention of pathological tau secretion without affecting the secretion of physiological tau. Furthermore, distinct extracellular tau species could be secreted in physiological and pathological conditions, species having the capacity to induce tau pathology being only secreted in the latter condition. In the present review, we will focus on the mechanisms and function of tau secretion in both physiological and pathological conditions and how this information can help to elaborate an efficient therapeutic strategy to prevent tau pathology and its propagation.

Keywords: extracellular tau; propagation; secretion; tau protein; tauopathies.

FIGURE 1

Secretory pathways of tau in physiological and pathological conditions. (1) The release of tau by ectosomes was only reported in physiological conditions. In both physiological and pathological conditions, tau could be released by (2) its translocation across the plasma membrane (PM), (3) exosomes, (4) the SNARE, SNAP-23, and the co-chaperone DNAJ/Hsc70 and (5) Rab7A, a Rab GTPase associated with late endosomes (LEs). (6) A correlation was noted between the fragmentation of the Golgi and an increase of tau secretion in pathological conditions. However, the pathway is not characterized yet. (7) Microglia were shown to release exosomes containing pathological tau in a tauopathy mouse model.

FIGURE 2

Therapeutic strategies for prevention of the propagation of tau pathology. (A) In physiological conditions, tau released at the pre-synaptic terminal presenting low phosphorylation levels, can interact with the receptors such as M1/M3 muscarinic receptors and activate signaling pathways involved in neuronal function. (B) In pathological conditions, extracellular pathological tau (phosphorylated and oligomeric) can interfere with synaptic function by inducing deficits in LTP, deficits in K+-evoked glutamate release, alterations in local Ca²⁺ dynamics and by altering the synaptic composition of NKA and AMPA receptors. The most (C) efficient therapeutic strategy would prevent the intracellular accumulation and aggregation of pathological tau by increasing its secretion (black arrows) and not that of physiological tau and would also involve the sequestration of pathological tau by an anti-tau antibody in the extracellular space (green rectangle). (D) Most pathways involved in tau secretion contribute to the release of tau in both physiological and pathological conditions. In such a case, the activation of tau secretion would not be confined to the affected regions and could also take place in non-affected regions leading to a decrease of intracellular physiological tau and an increase of extracellular physiological tau, which could be detrimental to healthy neurons. Furthermore, the capture of extracellular physiological tau by an anti-tau antibody could be detrimental in non-affected regions (red rectangle). In affected regions, both physiological (red rectangle) and pathological tau (green rectangle) could be released and captured by the anti-tau antibodies. If extracellular physiological tau plays a role in synaptic function and neuronal signaling, its capture could compromise neuronal recovery in the affected brain regions.